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Summary of the impact

Research by Professor Grassly and colleagues at Imperial College on the
epidemiology of poliovirus and the efficacy of new vaccines has played a
critical role in the thinking and strategy of the Global Polio Eradication
Initiative (GPEI). This research has supported the introduction of new
vaccines, guided the timing and location of vaccination campaigns and
influenced polio `endgame' policy. This is documented in the GPEI
Strategic Plan 2010-2012, where Imperial research informed 2 of the
4 `major lessons' concerning poliovirus epidemiology described in the
executive summary that led to changes in the programme. The research has
also informed our understanding of mucosal immunity induced by oral
poliovirus vaccines, and led to two clinical trials of the potential role
of inactivated vaccine to boost mucosal immunity. Results from one of
these trials were used to support the recent World Health Organisations
(WHO) recommendation for universal vaccination with inactivated vaccine
following the switch to bivalent oral vaccine in routine programmes.

In 2004, Professors Grassly and Fraser at Imperial College London
initiated a research collaboration with the Global Polio Eradication
Initiative (GPEI), which is headquartered at the World Health Organisation
(WHO), Geneva. The original intention of the research was to maximise the
utility of routine poliovirus surveillance data by providing more
sophisticated statistical and mathematical model-based analyses than were
in use at the time. Over time a vaccine epidemiology research group was
established at Imperial by Professor Grassly and the research effort has
expanded beyond secondary analysis of data to include clinical trials of
poliovirus vaccines. The group collaborates closely with field and
laboratory staff in polio affected countries, and has strong international
links, particularly in India. During 2004-2013 several of our research
findings with a significant impact on the strategies and success of the
GPEI can be highlighted:

1) In 2005 we found that the standard trivalent oral poliovirus vaccine
(OPV) has extremely poor efficacy in northern India, explaining the
persistence of polio at that time in the country despite frequent
vaccination campaigns (1).

2) We provided the first estimate of the efficacy of serotype 1
monovalent OPV, which was licensed in 2005, showing that this vaccine was
three times more efficacious per dose compared with the standard trivalent
OPV in northern India (2). This finding supported the widespread use of
this vaccine by the GPEI, and we have recently used similar methods to
demonstrate efficacy of bivalent OPV that was licensed in 2009 (3).

3) The clinical characteristics and attack rate for a vaccine-derived
poliovirus circulating in Nigeria were shown to be equivalent to that for
wild-poliovirus, making it clear that vaccine-derived polioviruses can
fully revert to neurovirulent and transmissible phenotypes (4).

4) Intestinal (mucosal) immunity, important for preventing infection and
transmission of polioviruses, was shown for the first time to wane over
time since vaccination with OPV (5).

5) Outbreaks of polio were shown to be predictable on the basis of known
risk factors, allowing strategic planning of the timing and scale of
pre-emptive vaccination campaigns (6).

Details of the impact

Impacts include: health and welfare; public policy and services;
international development Main beneficiaries include: patients; WHO; GPEI

The Global Polio Eradication Initiative (GPEI) is the largest coordinated
public health effort in history, with an `endgame' budget during 2013-2018
of $5.5 billion. The four spearheading partners of the GPEI are the WHO,
US Centers for Disease Control (CDC), Rotary International and UNICEF. The
vaccine epidemiology research group at Imperial College London has
provided critical information that has driven strategy at the GPEI and
helped to support polio eradication. In 2013 we were formally recognised
as the WHO collaborating institute on polio data analysis and modelling.

Perhaps most significantly, our research has provided evidence that
contributed to changing polio immunisation strategies in India, which
resulted in the elimination of infection from that country in 2011. The
GPEI Strategic Plan 2010-12 [1] notes that `Compounding the problem of
achieving sufficiently high population immunity to stop transmission in
western Uttar Pradesh, and possibly in central Bihar, is the compromised
efficacy of OPV compared with the rest of India15' (see page
18); citing our work demonstrating OPV failure in northern India (research
reference 2). Our subsequent demonstration of the greater efficacy of
monovalent and bivalent vaccines licensed in 2005 and 2009 respectively,
together with the geographic and targeted approaches described in the
Strategic Plan for 2010-2012, led to the eradication of polio from India,
with the last case reported in January 2011 (www.polioeradication.org).
Only three countries remain endemic for polio, and the group at Imperial
works closely with government and WHO staff in these countries and in WHO
headquarters to analyse surveillance data and optimise vaccination
strategy and campaign quality. For example, Dr O'Reilly was in northern
Afghanistan and Pakistan in July 2012 to monitor programme performance,
drawing from her findings on vaccination coverage and efficacy.

In the GPEI Strategic Plan 2010-2012, the Executive Summary identifies at
the outset four `major lessons learned', which each led to major changes
in the eradication programme. Two of these lessons drew directly from our
research findings on immunity induced by newly licensed poliovirus
vaccines and the epidemiology of poliovirus in endemic and re-infected
countries.

The first lesson learnt was that immunity thresholds to stop polio
differ, being higher in Asia than Africa, leading to a `"Geographic"
strategy, with OPV campaign and monitoring strategy tailored to local
circumstances. This was based on our findings that "The differential
progress by country towards polio eradication globally has long suggested
that the population immunity thresholds at which WPV transmission stops
can differ substantially between geographic areas, with implications for
programme strategy, planning, and prioritization" [1; see page 12, where
research references 1 and 4 are the cited evidence]. The resulting
`process indicators' in the Strategic Plan include targets based on our
estimates of vaccine-induced immunity [1; see page 15]. Our work is
therefore central to this new strategy and we provide updated analysis
when requested by the GPEI. As a result of these targeted approaches to
polio eradication and efforts to improve vaccination campaign coverage,
the global incidence of poliomyelitis is at an all time low (just 223
cases in 2012).

The second lesson drawing from our work was that `Routes of poliovirus
spread & outbreaks are now largely predictable', leading to, among
others, `Pre-planned, synchronized campaigns.' We had shown that polio
outbreaks in sub-Saharan Africa could be predicted with reasonable
accuracy 6 months ahead of time using a simple statistical (mathematical)
model (described in research reference 6 above). The Strategic Plan notes
that `In view of the substantial resource demands of implementing this
[pre-emptive vaccination campaign] strategy, a mathematical model has been
developed to help prioritize countries and areas based on the risk of both
an importation and a subsequent outbreak (Figure 4). Regular assessments
of polio immunity among the "WPV importation belt" countries using NP AFP
data, this model and other relevant information, will continue to inform
this prioritization.'; Figure 4 was provided by us, based on work
described in research reference 6 [1; see page 35]. We therefore continue
to provide assessments and forecasts of the risk of outbreaks in
sub-Saharan Africa to support immunization planning. These risk
assessments allow the programme to prioritize vaccination campaigns in a
time of serious resource constraints, maximising the cost-effectiveness of
the programme.

The World Health Assembly (May 2012) and WHO Strategic Advisory Group of
Experts (SAGE) recently recommended a switch from trivalent to bivalent
OPV during routine immunisation and global cessation of vaccination with
any serotype-2-containing OPV. The motivation for this switch came from
the recognition of the significant burden of vaccine-associated paralytic
poliomyelitis (VAPP) and vaccine-derived poliovirus outbreaks associated
with continued use of a serotype 2 OPV, when this serotype of
wild-poliovirus was eradicated over 10 years previously. Our work
demonstrating equivalent pathogenicity and transmissibility of serotype 2
vaccine-derived and wild-type poliovirus was an important piece of
evidence underlying this decision [2].

Our work demonstrating rapid waning of intestinal mucosal immunity
following vaccination with OPV and the detection of vaccine and wild-type
poliovirus in stool samples collected from OPV vaccinated children
provided motivation for two clinical trials on the use of inactivated
poliovirus vaccine (IPV) to boost intestinal immunity (Grassly et al. J
Infect Dis 2009, 2010, 2012). The first of these trials was led by WHO and
enrolled 990 children in northern India [3]. Results from this trial, for
which Professor Grassly is a co-investigator, were presented to WHO SAGE
in November 2012 for their consideration. They provided evidence for one
of the benefits of IPV that led to the WHO SAGE recommendation made in
January 2013 for universal vaccination with IPV at the time of the switch
from trivalent to bivalent OPV in routine programmes [4].

[4] WHO (2013). "Meeting of the Strategic Advisory Group of Experts on
immunization, November 2012 - conclusions and recommendations." Wkly
Epidemiol Rec 88: 1-16.http://www.who.int/wer/2013/wer8801.pdf
(page 6). Archived
on 4th November 2013.